Genome-Wide RNAi Screen Identifies Letml as a Mitochondrial Ca~(2+)H~+ Antiporter

摘要

Mitochondria are integral components of cellular calcium (Ca~(2+)) signaling. Calcium stimulates mitochondrial adenosine 5'-triphosphate production, but can also initiate apoptosis. In turn, cytoplasmic Ca~(2+) concentrations are regulated by mitochondria. Although several transporter and ion-channel mechanisms have been measured in mitochondria, the molecules that govern Ca~(2+) movement across the inner mitochondrial membrane are unknown. We searched for genes that regulate mitochondrial Ca~(2+) and H~+ concentrations using a genome-wide Drosophila RNA interference (RNAi) screen. The mammalian homolog of one Drosophila gene identified in the screen, Letml, was found to specifically mediate coupled Ca~(2+)/H~+ exchange. RNAi knockdown, overexpression, and liposome reconstitution of the purified Letml protein demonstrate that Letml is a mitochondrial Ca~(2+)/H~+ antiporter.